Data from the initial funding period of this grant have substantially informed us regarding the interaction between CVD and AD pathologies as they relate to the transitions between normal aging, MCI and dementia. These data suggest that CVD affects cognition through impairment of executive function, which in turn, adversely affects episodic memory performance. Anatomical evidence from these data strongly suggests that CVD influences executive function through white matter injury along specific tracts connecting parietal and frontal lobes and that the AD process also injures parietal subcortical white matter integrity, in addition to the more commonly recognized neuronal pathology. This information serves as the basis for a hypothetical disease model whereby CVD may act alone to cause impaired executive function (and possibly episodic memory impairment) or acts to amplify the cognitive effects of AD pathology. In addition, we hypothesize that both CVD and AD disease processes affect parietal-frontal connections through different mechanisms, and when they both occur in a given individual, will significantly increase the likelihood of future dementia. An important principal to our research is the recognition that both AD and CVD pathologies cause cognitive impairment through neuronal death or dysfunction. We also recognize that both diseases cause overlapping structural brain changes. For example, there is evidence that brain atrophy and WMH are the consequence of both AD and CVD pathologies, whereas MRI infarctions are strictly CVD and hippocampal atrophy is a strong, but not entirely pure indicator of AD. Unfortunately, until recently, it was impossible to dissociate these two disease processes on the basis of neuroimaging tools alone. A major advantage of our current study design is that-through use of PiB imaging-we can determine the presence or absence of cerebral amyloid, thereby allowing us to test the joint contributions of the AD and CVD processes on cognition without relying solely on MRI to make specific inferences regarding which structural brain changes relate to AD and which relate to CVD. The significance of our proposal continues to rest on the fact that CVD is currently the only treatable disease associated with cognitive impairment. We hope further understanding of how CVD impacts cognition will soon be used to develop clinical therapeutic trials that may reduce the incidence of cognitive impairment and dementia among our aging population. PUBLIC HEALTH RELEVANCE: This project seeks to extend current work evaluating the heterogeneous causes of mild cognitive impairment (MCI). Current work strongly suggests that MCI, including the amnestic subtype, results from the additive effects of cerebrovascular and Alzheimer's pathologies. This project is designed to identify the unique contributions of both pathologies to cognitive aging, MCI and risk for dementia.